Method of treatment

ABSTRACT

The present invention is directed to a method for promoting somking cessation or reduction or preventing relapse smoking, comprising administering an effective, non-toxic amount of paroxetine or a pharmaceutically acceptable salt or solvate thereof, to a human in need thereof.

This is a 371 of PCT/US99/13623, filed Jun. 16, 1999.

The present invention relates to a method for promoting smokingcessation or reduction or preventing relapse smoking, and especially tothe use of paroxetine in such treatment.

Pharmaceutical products with antidepressant and anti-Parkinsonproperties are described in U.S. Pat. Nos. 3,912,743 and 4,007,196. Anespecially important compound among those disclosed is paroxetine, the(−) trans isomer of4-(4′-fluorophenyl)-3-(3′,4′-methylene-dioxyphenoxymethyl)-piperidine(see Example 2 of U.S. Pat. No. 4,007,196). This compound is a SelectiveSerotonin Reuptake Inhibitor (SSRI). The hydrochloride salt ofparoxetine is approved for human use in therapy to treat inter aliadepression, obsessive compulsive disorder (OCD) and panic.

In commercial use, paroxetine hydrochloride is supplied as a crystallinehemihydrate (see EP-A-0223403 of Beecham Group). Various crystallineanhydrate forms are also known (see WO96/24595 of SmithKline Beechamplc).

SSRI compounds such as fluoxetine and sertraline have been proposed foruse in treating chemical dependency (see U.S. Pat. No. 5,130,338)including nicotine withdrawal symptons (see U.S. Pat. No. 4,940,585 and4,999,382). However various clinical studies have suggested that whilefluoxetine had favourable influences on factors associated with smokingcessation such as weight gain and alcohol consumption, it did notenhance smoking cessation rates (see Mizes et al, Psychopharmacol.Bull.32, No.3, 491, 1996; Sullivan et al, J.Clin.Pharmacol. 29, No.9, 850,1989).

It has now been surprisingly discovered that paroxetine has potentialtherapeutic utility as a medicament for promoting smoking cessation orreduction or preventing relapse smoking.

Accordingly, the present invention provides a method for promotingsmoking cessation or reduction or preventing relapse smoking, whichmethod comprises administering an effective, non-toxic amount ofparoxetine or a pharmaceutically acceptable salt or solvate there of, tohuman in need thereof.

The present invention also provides the use of paroxetine or apharmaceutically acceptable salt or solvate thereof in the manufactureof a medicament for use in promoting smoking cessation or reduction orpreventing relapse smoking.

Paroxetine used in the present invention is suitably in the form of thefree base or a pharmaceutically acceptable salt thereof. A preferredpharmaceutically acceptable salt of paroxetine is crystallinehydrochloride. Suitable procedures for preparing paroxetinehydrochloride include those mentioned in U.S. Pat. Nos. 4,009,196,4,721,723, 4,902,801, 4,861,893 and 5,039,803 and PCT/GB93/00721.Especially preferred is the hemi-hydrate, prepared as EP-A-0223403.

A medicament, for use in promoting smoking cessation or reduction orpreventing relapse smoking may be prepared by admixture of paroxetine ora pharmaceutically acceptable salt or solvate thereof with anappropriate carrier, which may contain a diluent, binder, filler,disintegrant, flavouring agent, colouring agent, lubricant orpreservative in conventional manner.

Preferably, the medicament is in unit dosage form and in a form adaptedfor use in the medical or veterinarial fields. For example, suchpreparations may be in a pack form accompanied by written or printedinstructions for use in promoting smoking cessation or reduction orpreventing relapse smoking.

The suitable dosage range for paroxetine or a pharmaceuticallyacceptable salt or solvate depends on the severity of the smokingdisorders and on the condition of the patient. It will also depend,inter alia, upon the relation of potency to absorbability and thefrequency and route of administration.

Paroxetine or a pharmaceutically acceptable salt or solvate thereof maybe formulated for administration by any route, and examples are oral,sub-lingual, rectal, topical, trans-dermal, parenteral, intravenous orintramuscular administration. Preparations may, if desired, be designedto give slow release of the paroxetine or a pharmaceutically acceptablesalt or solvate thereof. The medicaments may additionally contain otheractive ingredients useful in methods of promoting smoking cessation orreduction or preventing relapse smoking, such as nicotine or apharmaceutically acceptable derivative thereof.

The medicaments may, for example, be in the form of tablets, capsules,sachets, vials, powders, granules, lozenges, reconstitutable powders, orliquid preparations, for example solutions or suspensions, orsuppositories.

The medicaments, for example those suitable for oral administration, maycontain conventional excipients such as binding agents, for examplesyrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone;fillers, for example lactose, sugar, maize-starch, calcium phosphate,sorbitol or glycerine; tabletting lubricants, for example magnesiumstearate; disintegrants, for example starch, polyvinylpyrrolidone,sodium starch glycollate or microcrystalline cellulose; orpharmaceutically acceptable setting agents such as sodium laurylsulphate.

Solid medicaments may be obtained by conventional methods of blending,filling, tabletting or the like. Repeated blending operations may beused to distribute paroxetine or a salt or solvate thereof throughoutthose medicaments employing large quantities of fillers. When themedicament is in the form of a tablet, powder, or lozenge, any carriersuitable for formulating solid pharmaceutical compositions may be used,examples being magnesium stearate, starch, glucose, lactose, sucrose,rice flour and chalk. Tablets may be coated according to methods wellknown in normal pharmaceutical practice, in particular with an entericcoating. The medicament may also be in the form of an ingestiblecapsule, for example of gelatin containing paroxetine or a salt thereofif desired with a carrier or other excipients.

Medicaments for oral administration as liquids may be in the form of,for example, emulsions, syrups, or elixirs, or may be presented as a dryproduct for reconstitution with water or other suitable vehicle beforeuse. Such liquid medicaments may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel, hydrogenated edible fats; emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia; aqueous or non-aqueousvehicles, which include edible oils, for example almond oil,fractionated coconut oil, oily esters, for example esters of glycerine,or propylene glycol, or ethyl alcohol, glycerine, water or normalsaline; preservatives, for example methyl or propyl p-hydroxybenzoate orsorbic acid; and if desired conventional flavouring or colouring agents.

Paroxetine or a pharmaceutically acceptable salt or solvate thereof mayalso be administered by a non-oral route. In accordance with routinepharmaceutical procedure, the medicaments may be formulated, for examplefor rectal administration as a suppository. They may also be formulatedfor presentation in an injectable form in an aqueous or non-aqueoussolution, suspension or emulsion in a pharmaceutically acceptableliquid, e.g. sterile pyrogen-free water or a parenterally acceptable oilor a mixture of liquids. The liquid may contain bacteriostatic agents,anti-oxidants or other preservatives, buffers or solutes to render thesolution isotonic with the blood, thickening agents, suspending agentsor other pharmaceutically acceptable additives. Such forms will bepresented in unit dose form such as ampoules or disposable injectiondevices or in multi-dose forms such as a bottle from which theappropriate dose may be withdrawn or a solid form or concentrate whichcan be used to prepare an injectable formulation.

As mentioned hereinbefore, the effective dose of the paroxetine orpharmaceutically acceptable salt or solvate depends on the severity ofthe smoking disorders to be treated, the condition of the patient and onthe frequency and route of administration. A unit dose will generallycontain from 2 to 1000 mg and preferably will contain from 30 to 500 mg,in particular 20, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.The composition may be administered once or more times a day, forexample 2, 3 or 4 times daily, and the total daily dose for a 70 kgadult will normally be in the range 100 to 3000 mg. Preferably the unitdose will contain from 2 to 20 mg of paroxetine (calculated as freebase) and be administered in multiples, if desired, to give thepreceding daily dose.

Preferably the present invention is practised using a controlled releaseor delayed release formulation containing paroxetine or apharmaceutically acceptable salt thereof.

By controlled release is meant any formulation technique wherein releaseof the active substance from the dosage from is modified to occur at aslower rater than that from an immediate release product, such as aconventional swallow tablet or capsule.

By delayed release is meant any formulation technique wherein release ofthe active substance from the dosage form is modified to occur at alater time than that from a conventional immediate release product. Thesubsequent release of active substance from a delayed releaseformulation may also be controlled as defined above.

Examples of controlled release formulations which are suitable forincorporating paroxetine are described in:

Sustained Release Medications, Chemical Technology Review No. 177. Ed.J. C. Johnson. Noyes Data Corporation 1980.

Controlled Drug Delivery, Fundamentals and Applications, 2nd Edition.Eds. J. R. Robinson, V. H. L. Lee. Mercel Dekkes Inc. New York 1987.

Examples of delayed release formulations which are suitable forincorporating paroxetine are described in:

Remington's Pharmaceutical Sciences 16th Edition, Mack PublishingCompany 1980, Ed. A. Osol.

Such controlled release formulations are preferably formulated in amanner such that release of active substance such as paroxetine iseffected predominantly during the passage through the stomach and thesmall intestine, and delayed release formulations are preferablyformulated such that release of active substance such as paroxetine isavoided in the stomach and is effected predominantly during passagethrough the small intestine

Said formulations are preferably formulated such that the release of theactive substance is predominantly 1½ to 3 hours post ingestion.

Preferred formulations are ultimately enteric coated tablets or caplets,wax or polymer coated tablets or caplets or time-release matrices, orcombinations thereof.

Particularly preferred formulations are described in U.S. Pat. No.5,102,666.

Thus, a particular aspect of the invention involves use of a polymericcontrolled release composition comprising a reaction complex formed bythe interaction of (1) a calcium polycarbophil component which is awater-swellable, but water insoluble, fibrous cross-linkedcarboxy-functional polymer, said polymer containing (a) a plurality ofrepeating units of which at least about 80% contain at least onecarboxyl functionality, and (b) about 0.05 to about 1.5% cross-linkingagent substantially free from polyalkenyl polyether, said percentagesbeing based upon the weights of unpolymerised repeating unit andcross-linking agent, respectively, with (2) water, in the presence ofparoxetine. The amount of calcium polycarbophil present is from about0.1 to about 99% by weight, for example about 10%. The amount of activeagent present is from about 0.0001 to about 65% by weight, for examplebetween about 5 and 20%. The amount of water present is from about 5 toabout 200% by weight, for example between about 5 and 10%. Theinteraction is carried out at a pH of between about 3 and about 10, forexample about 6 to 7. The calcium polycarbophil is originally present inthe form of a calcium salt containing from about 5 to about 25% calcium.

Further particularly preferred formulations are described in U.S. Pat.No. 5,422,123.

Thus, a further particular aspect involves use of a system for thecontrolled release of paroxetine, comprising (a) a deposit-corecomprising an effective amount of paroxetine and having definedgeometric form, and (b) a support-platform applied to said deposit-core,wherein said deposit-core contains paroxetine, and at least one memberselected from the group consisting of (1) a polymeric material whichswells on contact with water or aqueous liquids and a gellable polymericmaterial wherein the ratio of the said swellable polymeric material tosaid gellable polymeric material is in the range 1:9 to 9:1, and (2) asingle polymeric material having both swelling and gelling properties,and wherein the support-platform is an elastic support, applied to saiddeposit-core so that it partially covers the surface of the deposit-coreand follows changes due to hydration of the deposit-core and is slowlysoluble and/or slowly gellable in aqueous fluids. The support-platformmay comprise polymers such as hydroxypropylmethylcellulose, plasticizerssuch as a glyceride, binders such as polyvinylpyrrolidone, hydrophilicagents such as lactose and silica, and/or hydrophobic agents such asmagnesium stearate and glycerides. The polymer(s) typically make up 30to 90% by weight of the support-platform, for example about 35 to 40%.Plasticizer may make up at least 2% by weight of the support-platform,for example about 15 to 20%. Binder(s), hydrophilic agent(s) andhydrophobic agent(s) typically total up to about 50% by weight of thesupport-platform, for example about 40 to 50%.

The present invention further provides a pharmaceutical composition foruse in promoting smoking cessation or reduction or preventing relapsesmoking which comprises an effective amount of paroxetine or apharmaceutically acceptable salt or solvate thereof and apharmaceutically acceptable carrier. Such compositions may be preparedin the manner as hereinbefore described.

The paroxetine product of the present invention may optionally becoadministered with a nicotine-containing smoking cessation aid such asa patch, gum, or inhalator.

The following Examples disclose suitable pharmaceutical compositions foruse in the present invention.

EXAMPLE 1

(Hydrophilic Matrix)

% w/w Intragranular Paroxetine Hydrochloride 11.45 Methocel E5 1.25Lactose 12.3 Extragranular Methocel K100LV 30.0 Lactose 44.0 MagnesiumStearate 1.0 TOTAL 100.0

EXAMPLE 2

(Hydrophilic Matrix)

% w/w Intragranular Paroxetine Hydrochloride 11.45 Methocel E5 1.25Lactose 12.3 Extragranular Methocel K100LV 27.5 Methocel K4M 7.5 Lactose39.0 Magnesium Stearate 1.0 TOTAL 100.0

EXAMPLE 3

(pH Sensitive Coat on Immediate Release Core)

% w/w Tablet Core Paroxetine Hydrochloride 11.45 Lactose 64.05Microcrystalline Cellulose 20.0 Sodium Starch Glycollate 4.0 MagnesiumStearate 0.5 TOTAL 100.0 Tablet Coating (apply approximately 6-10% oftablet core weight) Hydroxypropylmethylcellulose Phthalate 90.0Triacetin 10.0

EXAMPLE 4

(pH Sensitive Coat on Immediate Release Core)

Tablet Core as in Example 3

% w/w Tablet Coating (apply approximately 6-10% of tablet core weight)Cellulose Acetate Phthalate 90.0 Diethyl Phthalate 10.0

EXAMPLE 5

(Controlled Release Coating on Immediate Release Core)

Tablet Core as in Example 3

% w/w Tablet Coating (apply approximately 5-12% of tablet core weight)Eudragit RS 100 86.0 Dibutyl Phthalate 10.0 Talc 4.0 FD&C Yellow No. 60.01

EXAMPLE 6

(pH Sensitive Coat on Controlled Release Core.)

Tablet Core as in Example 3

Tablet Coating as in Example 3

EXAMPLE 7

(Encapsulated Controlled Release Coated Beads)

% w/w (approx) Pellet Non Pareil Seed 30 Paroxetine Hydrochloride 40Gelatin 8 Lactose 20 Talc 2 % w/w Coating Glycerylmonostearate 36.6Glyceryldistearate 53.4 White Wax 10.0

EXAMPLE 8

(Controlled Release Bilayer Tablet)

Component mg/tablet Function Active Layer Paroxetine Hydrochloride22.89* Active Methocel K4M 15.00 Hydrogel polymer Lactose monohydrate62.0 Hydrophilic agent Polyvinylpyrrolidone 3.0 Binder Magnesiumstearate 1.0 Hydrophobic agent Syloid 244 1.0 Hydrophilic agent Supportplatform Compritol 888 15.04 Plasticizer Lactose monohydrate 29.32Hydrophilic agent Polyvinylpyrrolidone 4.0 Binder Magnesium stearate1.52 Hydrophobic agent Methocel E5 29.32 Hydrogel polymer Iron oxide0.08 Colourant Total tablet weight 184.89 mg *Equivalent to 20 mgparoxetine as free base.

The powder blend for each layer was wet granulated in a high shearmixer/granulator and dried in a fluid bed drier. The bilayer tabletswere compressed on a Manesty triple layer press.

EXAMPLE 9

(Enteric Coated Calcium Polycarbophil Formulation)

Component mg/tablet Function Core Paroxetine Hydrochloride  22.89*Active Calcium polycarbophil  20.00 Matrix Lactose anhydrous 146.11Hydrophilic agent/diluent Polyvinylpyrrolidone 10.0 Binder Magnesiumstearate  1.0 Hydrophobic agent/lubricant Water**   0.024 Granulatingliquid Enteric coat Eudragit  22.19 Polymer Talc  1.53 LubricantTriethyl citrate  1.00 Plasticizer Water** 24.6 Diluent Film coat Opadrypink 10.5 Film coat Water** 94.5 Diluent Polish coat Opadry clear  0.750 Water** 29.3 Diluent *Equivalent to 20 mg paroxetine as freebase. **Removed during processing.

The core constituents were wet granulated in a high shearmixer/granulator, and dried in a fluid bed drier. The magnesium stearatewas then added and the mixture processed in a low shear mixer. The mixwas then compressed on a B type rotary tablet press. Coating was carriedout using an Accela cota.

EXAMPLE 10

(Controlled Release Bilayer Tablet)

Component mg/tablet Function Active Layer Paroxetine Hydrochloride22.89* Active Methocel K4M 20.00 Hydrogel polymer Lactose monohydrate60.0 Hydrophilic agent Polyvinylpyrrolidone 5.0 Binder Magnesiumstearate 1.0 Hydrophobic agent Syloid 244 1.0 Hydrophilic agent Supportplatform Compritol 888 14.72 Plasticizer Lactose monohydrate 30.60Hydrophilic agent Polyvinylpyrrolidone 2.80 Binder Magnesium stearate0.80 Hydrophobic agent Methocel E5 30.60 Hydrogel polymer Syloid 2440.40 Hydrophilic agent Iron oxide 0.08 Colourant Total tablet weight189.89 mg *Equivalent to 20 mg paroxetine as free base. The process wasas described in Example 8.

EXAMPLE 11

(Controlled Release Bilayer Tablet)

Component mg/tablet Function Active Layer Paroxetine Hydrochloride 22.89Active Methocel K4M 15.00 Hydrogel poymer Lactose monohydrate 63.31Hydrophilic agent Polyvinylpyrrolidone 2.0 Binder Magnesium stearate 1.0Hydrophobic agent Syloid 244 0.40 Hydrophilic agent Support platform -as in Example 10. Total tablet weight 184.60 mg

The process was as described in Example 8.

EXAMPLE 12

(Enteric Coated Controlled Release Bilayer Tablet)

Component mg/tablet Function Active Layer Paroxetine Hydrochloride28.61* Active Methocel K4M 18.75 Hydrogel polymer Lactose monohydrate79.14 Hydrophilic agent Polyvinylpyrrolidone 2.50 Binder Magnesiumstearate 1.25 Hydrophobic agent Syloid 244 0.50 Hydrophilic agentSupport platform Compritol 888 15.04 Plasticizer Lactose monohydrate30.50 Hydrophilic agent Polyvinylpyrrolidone 4.00 Binder Magnesiumstearate 0.80 Hydrophobic agent Methocel E5 29.32 Hydrogel polymerSyloid 244 0.32 Hydrophilic agent Iron oxide 0.02 Colourant Entericcoating Eudragit 13.27 Polymer Talc 3.31 Lubricant Triethyl citrate 1.33Plasticizer Water** 36.25 Diluent Total tablet weight 228.66 mg

The process was as described in Example 9.

EXAMPLE 13

The following are mixed together in a conventional manner and compressedinto tablets of ca. 300 mg weight containing ca. 20 mg of paroxetine(calculated as the free base).

Paroxetine hydrochloride hemihydrate 228.8 g Dibasic calcium phosphatedihydrate 2441.2 g Hydroxypropylmethyl cellulose 2910 150.0 g Sodiumstarch glycollate 150.0 g Magnesium Stearate 30.0 g Total tablet weight3000.0 g

What is claimed is:
 1. A method for promoting smoking cessation orreduction or preventing relapse smoking, which method comprisesadministering an effective amount of paroxetine or a pharmaceuticallyacceptable salt or solvate there of, to a human in need thereof.
 2. Themethod according to claim 1 wherein the paroxetine is in the form of thefree base or a pharmaceutically acceptable salt thereof.
 3. The methodaccording to claim 2 wherein the pharmaceutically acceptable salt ofparoxetine is a crystalline hydrochloride.
 4. The method according toclaim 3 wherein the hydrochloride is the hemi-hydrate.
 5. The methodaccording to claim 1 wherein the paroxetine is administered in acontrolled release or delayed release formulation.
 6. The methodaccording to claim 5 wherein the paroxetine is administered orally. 7.The method according to claim 6 wherein the controlled release ordelayed release formulation comprises (a) a deposit-core comprising aneffective amount of paroxetine and having defined geometric form, and(b) a support-platform applied to said deposit-core, wherein saiddeposit-core contains paroxetine, and at least one member selected fromthe group consisting of (1) a polymeric material which swells on contactwith water or aqueous liquids and a gellable polymeric material whereinthe ratio of the said swellable polymeric material to said gellablepolymeric material is in the range 1:9 to 9:1, and (2) a singlepolymeric material having both swelling and gelling properties, andwherein the support-platform is an elastic support, applied to saiddeposit-core so that it partially covers the surface of the deposit-coreand follows changes due to hydration of the deposit-core and is slowlysoluble and/or slowly gellable in aqueous fluids.
 8. The methodaccording to claim 1 wherein the paroxetine is coadministered with anicotine-containing smoking cessation aid.